|Publication number||US6877528 B2|
|Application number||US 10/179,586|
|Publication date||Apr 12, 2005|
|Filing date||Jun 24, 2002|
|Priority date||Apr 17, 2002|
|Also published as||US7069943, US8210209, US8623295, US9011797, US20030196714, US20050109410, US20060278288, US20120015442, US20120261013, WO2003088733A2, WO2003088733A3, WO2003088733A8|
|Publication number||10179586, 179586, US 6877528 B2, US 6877528B2, US-B2-6877528, US6877528 B2, US6877528B2|
|Inventors||John Richard Gilbert, Sebastian Böhm, Manish Deshpande|
|Original Assignee||Cytonome, Inc.|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (17), Referenced by (62), Classifications (61), Legal Events (12)|
|External Links: USPTO, USPTO Assignment, Espacenet|
This application claims priority to U.S. Provisional Patent Application No. 60/373,256 entitled “Microfluidic System Including a Bubble Valve for Regulating Fluid Flow Through a Microchannel” filed Apr. 17, 2002; and is related to application Ser. No. 10/665,885, entitled “Method and Apparatus for Sorting Particles”, filed herewith. The contents of both applications are herein incorporated by reference.
The present invention relates to microscale fluid handling devices and systems. More particularly, the present invention relates to a method and system for controlling liquid flow in a microchannel by the introduction of a gas bubble to a microfluidic system.
In the chemical, biomedical, bioscience and pharmaceutical industries, it has become increasingly desirable to perform large numbers of chemical operations, such as reactions, separations and subsequent detection steps, in a highly parallel fashion. The high throughput synthesis, screening and analysis of (bio)chemical compounds, enables the economic discovery of new drugs and drug candidates, and the implementation of sophisticated medical diagnostic equipment. Of key importance for the improvement of the chemical operations required in these applications are an increased speed, enhanced reproducibility, decreased consumption of expensive samples and reagents, and the reduction of waste materials.
Microfluidic devices and systems provide improved methods of performing chemical, biochemical and biological analysis and synthesis. Microfluidic devices and systems allow for the performance of multi-step, multi-species chemical operations in chip-based micro chemical analysis systems. Chip-based microfluidic systems generally comprise conventional ‘microfluidic’ elements, particularly capable of handling and analyzing chemical and biological specimens. Typically, the term microfluidic in the art refers to systems or devices having a network of processing nodes, chambers and reservoirs connected by channels, in which the channels have typical cross-sectional dimensions in the range between about 1.0 μm and about 500 μm. In the art, channels having these cross-sectional dimensions are referred to as ‘microchannels’.
By performing the chemical operations in a microfluidic system, potentially a number of the above-mentioned desirable improvements can be realized. Downscaling dimensions allows for diffusional processes, such as heating, cooling and passive transport of species (diffusional mass-transport), to proceed faster. One example is the thermal processing of liquids, which is typically a required step in chemical synthesis and analysis. In comparison with the heating and cooling of liquids in beakers as performed in a conventional laboratory setting, the thermal processing of liquids is accelerated in a microchannel due to reduced diffusional distances. Another example of the efficiency of microfluidic systems is the mixing of dissolved species in a liquid, a process that is also diffusion limited. Downscaling the typical dimensions of the mixing chamber thereby reduces the typical distance to be overcome by diffusional mass-transport, and consequently results in a reduction of mixing times. Like thermal processing, the mixing of dissolved chemical species, such as reagents, with a sample or precursors for a synthesis step, is an operation that is required in virtually all chemical synthesis and analysis processes. Therefore, the ability to reduce the time involved in mixing provides significant advantages to most chemical synthesis and analysis processes.
Another aspect of the reduction of dimensions is the reduction of required volumes of sample, reagents, precursors and other often very expensive chemical substances. Milliliter-sized systems typically require milliliter volumes of these substances, while microliter sized microfluidic systems only require microliters volumes. The ability to perform these processes using smaller volumes results in significant cost savings, allowing the economic operation of chemical synthesis and analysis operations. As a consequence of the reduced volume requirement, the amount of chemical waste produced during the chemical operations is correspondingly reduced.
In microfluidic systems, regulation of minute fluid flows through a microchannel is of prime importance, as the processes performed in these systems highly depend on the delivery and movement of various liquids such as sample and reagents. A flow control device may be used to regulate the flow of liquid through a microchannel. Regulation includes control of flow rate, impeding of flow, switching of flows between various input channels and output channels as well as volumetric dosing.
U.S. Pat. No. 6,062,681 describes a bubble valve for a liquid flow channel in which the flow of a liquid is controlled by the generation of a gas bubble in the channel using a heater placed in the liquid. As the heater is activated, a bubble is formed which can be enlarged or reduced in size by increasing or decreasing, respectively, the temperature of the heater. The described system presents a number of disadvantages, namely, the required power to operate the valve and the inherent requirement that liquid in the channel be heated upon passing the valve. Even small increases in liquid temperature, by only a couple of degrees, can have disastrous effects on the highly heat sensitive biochemical substances present in the liquids to be controlled in many microfluidic systems. In addition, the required on-chip electric circuitry for the heater increases the complexity of the described valve and consequently results in unacceptably high costs, particularly if the fluidic system employing the bubble valve only used for a single application.
Other valves in the prior art use electrochemical means to produce a bubble in a liquid.
The present invention provides a bubble valve for controlling, regulating or varying fluid flow through a microfluidic system. The bubble valve regulates fluid flow through a channel using an externally operated mechanical or pneumatic actuator. The actuator causes a deflection of a fluid meniscus into the interior of the channel to regulate liquid flow. The actuator may mechanically force a gas bubble into a fluid carrying microchannel to inhibit liquid flow or to cause liquid flow by applying a sufficiently high pressure to the meniscus. The bubble valve effectively controls the flow of liquids in microfluidic systems, without heating the fluid and without complex on-chip circuitry.
The microfluidic system includes a microchannel and a sealed, gas-filled reservoir positioned adjacent to and connected to the microchannel. The gas filled reservoir has a movable wall and a meniscus formed by a liquid in the microchannel that forms an interface between the reservoir and the microchannel interior. The meniscus may form a portion of the side wall of the microchannel. An external mechanical actuator may be used to deflect the movable wall of the reservoir. As the movable wall is deflected, the volume of the reservoir decreases and the gas pressure inside the reservoir increases, causing the meniscus to deflect into the microchannel, thereby modifying the cross-sectional area of the microchannel and consequently varying the flow of liquid through the channel. The increased pressure in the reservoir pushes gas from the reservoir into the microchannel. The gas may result in a local gas bubble being forced into the microchannel from the gas-filled reservoir. The resulting gas bubble occupies a portion of the cross-section of the channel, allowing liquid flow through the channel to be effectively controlled by controlling the size of the gas bubble via the external actuator.
The meniscus may comprise a virtual wall formed in a side wall of the microchannel. The virtual wall is a meniscus formed by a liquid in the microchannel that fills an aperture formed in the side wall of the microchannel and essentially replaces the removed portion of the side wall without affecting the properties of liquid flow through the channel. A gas bubble can be forced into the channel by applying a gas pressure at the opening using an external pneumatic actuator. The gas pressure forces the meniscus inside the channel, which varies the flow of liquid through the channel interior.
According to one embodiment, the microchannel includes a hydrophobic patch spanning the width of the microchannel at the location where the gas bubble is introduced to enhanced on-off switching of the bubble valve. The hydrophobic patch anchors the bubble in a particular location in the microchannel. If the introduced gas bubble covers the whole area of the patch, the bubble is effectively retained by capillary forces and blocks any liquid flow up to a certain pressure difference, depending on the level of hydrophobicity of the patch.
Alternatively or in combination with a hydrophobic patch, the microchannel can be locally shaped into a cavity for receiving and anchoring the gas bubble. By providing an appropriate cavity, the bubble can be kept in place during operation, reducing the risk that the gas bubble is carried away with the liquid.
According to one aspect of the invention, a microfluidic device is provided. The microfluidic device comprises a microchannel having an interior bounded by a side wall and a valve for regulating the flow of fluid through the microchannel. The valve comprises a gas-filled reservoir, a fluid meniscus interfacing the reservoir and the interior and an actuator for varying the volume of the reservoir to increase an internal pressure of the reservoir to vary the flow of liquid through the channel.
According to another aspect, a microfluidic device is provided, comprising a first plate having a groove formed therein defining a microchannel, a second plate for enclosing the microchannel and a flexible membrane. The second plate is bonded to the first plate and has an aperture adjacent to the groove sized and dimensioned to form a meniscus when the microchannel is filled with a liquid. The aperture defines a reservoir adjacent to the microchannel, wherein the meniscus forms an interface between the microchannel and the reservoir. The flexible membrane is bonded to the second plate to seal the reservoir.
According to another aspect, a method of making a bubble valve is provided, the method comprises providing a microchannel having an interior bounded by a side wall, an aperture formed in the side wall and a valve chamber adjacent to the aperture in communication with the interior, filling the microchannel with a liquid to form a meniscus of the liquid in the aperture, whereby the step of filling traps a gas in the valve chamber and providing an actuator for increasing the pressure in the valve chamber to deflect the meniscus into the interior.
According to yet another aspect, a method of making a bubble valve is provided. The method comprises providing a microchannel having an interior bounded by a side wall, an aperture formed in the side wall and a valve chamber adjacent to the aperture in communication with the interior, filling the microchannel with a liquid to form a meniscus of the liquid in the aperture and applying and sealing an actuator comprising a chamber to a top surface of the microchannel to form a gas-filled chamber adjacent to the meniscus. The actuator varies the pressure in the gas-filled chamber to deflect the meniscus into the interior, thereby regulating fluid flow.
According to still another aspect, a microfluidic device is provided comprising a microchannel having an interior bounded by a side wall, a bubble valve for creating and injecting a bubble into the microchannel interior to regulate fluid flow through the microchannel and a hydrophobic patch for retaining the bubble in a predetermined position in the microchannel interior.
According to yet another aspect a bubble valve in a particle sorting device for separating particles having a predetermined characteristic from particles not having a predetermined characteristic is provided. The bubble valve comprises a gas-filled reservoir, a side channel in communication with a channel through which a stream of particles in a carrier fluid passes, wherein the carrier fluid forms a meniscus in the side channel adjacent to the gas-filled reservoir and an actuator for deflecting the meniscus to create a pressure pulse to selectively deflect a particle having the predetermined characteristic from the stream of particles.
According to still another aspect, a method of varying an electrical resistance in a microchannel is provided. The method comprises generating a bubble and injecting the bubble into a liquid in the microchannel, whereby the bubble varies the electrical resistance of the microchannel.
According to yet another aspect, an electrophoretic system is provided, comprising an electrokinetically operated microchannel, a sample well for providing an sample to the microchannel, a voltage source and a bubble valve for injecting a bubble into the microchannel to vary the electrical resistance of the microchannel.
According to a final aspect of the invention, an electrokinetic column to column switch is provided, comprising a first electrokinetically operated microchannel, a second electrokinetically operated microchannel in communication with the first electrokinetically operated microchannel and a bubble valve for selectively blocking flow from the first electrokinetically operated microchannel to the second electrokinetically operated microchannel by selectively injecting a bubble into a microchannel.
The present invention provides an improved bubble valve for controlling fluid flow through a microchannel in a microfluidic system. The invention further provides a method of forming the bubble valve. The bubble valve of the present invention can be applied in numerous microfluidic systems for controlling and switching fluid flows. Examples of suitable applications include, but are not limited to: flow cytometry, column switching, 2-D separations, cell or particle sorting applications on a chip, regulating pressurized fluid flows including on-off switching, regulating electrokinetic fluid flows and electrokinetically induced processes including on-off switching and electrokinetic sample injection and channel to channel switching.
The microfluidic system 100 includes a bubble valve 10, 10′ shown in
According to an alternate embodiment, the bubble valve is formed by a meniscus in a separate side channel that communicates with and intersects a microchannel through which a liquid to be controlled flows. One skilled in the art will recognize that the meniscus can be located at any location relative to the microchannel through which liquid flows.
The gas-filled reservoir may be formed when filling the microchannel having an aperture in a side wall and a reservoir formed adjacent to the aperture. An empty microchannel may be filled with liquid, forming the meniscus in the aperture, which traps the gas that forms the gas bubble and forms a gas pocket in the reservoir adjacent to the meniscus. The creation of the gas pocket on filling provides a sterile gas bubble and reduces contaminants in the system. Alternatively, the air pocket may be created by introducing a gas to the reservoir after filling of the microchannel.
The bubble valve 10 operates to control the flow of liquid through the microchannel 21. A meniscus is formed in the aperture 31, which interfaces with and separates the microchannel interior from the reservoir 70. According to the embodiment shown in
After the microchannel is filled with a liquid 60, the bubble valve 10 is ready for operation.
The slot 31 b may be sized and dimensioned to form a “virtual wall” in the microchannel. As used herein, “virtual wall” refers to the meniscus 80 formed by the first liquid 60 in the aperture formed in the side wall of the microchannel 20, which essentially replaces the removed portion of the side wall without affecting the properties of the microchannel. The meniscus surface can be, although not required, substantially co-planar with the wall of the microchannel in which the meniscus is formed. The word “virtual” is chosen to express the effect that the overall liquid flow through the microchannel 21 of the microfluidic system 100 is not influenced by the virtual wall, i.e. the flow of liquid in the microfluidic system having a virtual wall is substantially identical to the flow of liquid through an identical microfluidic system in which no virtual wall is present. One of ordinary skill will recognize that the meniscus may be convex or concave, depending on the appropriate system pressure.
When the actuator 50 is actuated, the bubble valve 10 switches to a “pinched” state, as shown in
When the actuator is fully actuated, the bubble valve 10 is switched to a closed state, as illustrated in
According to one embodiment, the bubble valve 10 may be used as a check valve for regulating pressure in the microchannel. When the pressure in the microchannel exceeds a maximum breaking pressure, the bubble collapses, opening the valve and allowing fluid to flow through the channel, thereby reducing the pressure in the microchannel. The breaking pressure depends on the hydrophobicity of the hydrophobic patch 22, as well as the geometry of the microchannel.
Alternatively or in combination with the hydrophobic patch 22, the microchannel 21 can be locally shaped into a cavity for receiving and anchoring the gas bubble 81. By providing an appropriate cavity, the bubble can be kept in place during operation, reducing the risk that the gas bubble is carried away with the liquid.
According to the embodiments shown in
Upon filling of the microchannel 21 with a liquid, a virtual wall 32 a is formed in virtual wall opening 32. As shown in
To switch the valve to a ‘closed’ state, as shown in
In the injection phase, valves 10 a, 10 b, 10 c and 10 d are substantially in the open position, allowing passage of electrical current up to a required level for injection (
Immediately after the injection phase, a plug of sample is injected and separated in the separation column 115 a (microchannel which runs horizontally in figure) by closing bubble valves 10 a, 10 d and 10 c and opening valves 10 b and 10 e. Now the total voltage difference is applied longitudinally over the separation channel, resulting in the separation of the constituents in the sample (
At first, the two electrokinetically operated microchannel 215 a and electrokinetically operated microchannel 215 b are operated independently and the connecting bubble valve 10 b is in the ‘closed’ state whilst bubble valve 10 a and bubble valve 10 c are in the ‘open’ state. To electrokinetically transfer substance from electrokinetically operated microchannel 215 a to the electrokinetically operated microchannel 215 b, bubble valve 10 a and bubble valve 10 c are switched to the closed state, and the connecting bubble valve 10 b is opened momentarily to allow passage of an amount of substance from the electrokinetically operated microchannel 215 a to the electrokinetically operated microchannel 215 b. The amount transferred depends directly upon the time bubble valve 10 b is opened. After the required amount of substance is transferred, the connecting bubble valve 10 b is closed and the bubble valve 10 a and bubble valve 10 b are opened again.
In a suspension introduced by the first supply duct 162, two types of particles can be distinguished, normal particles 180 a and particles of interest 180 b. The flow rates in both branches 172 a and 172 b are adjusted so that the stream of particles normally flows through the second branch 172 b. Upon sensing the predetermined characteristic in the particles in the measurement region 182 a, the detector 182 b raises a signal. The external actuator 176 activates the bubble valves 10 a, 10 b when signaled by the detector 182 b in response to sensing the predetermined characteristic, to create a flow disturbance in the measurement duct 166 between the sideway passages 174 a, 174 b, to deflect the particle having the predetermined characteristic so that it flows down the first branch duct 172 a rather than the second branch duct 172 b. The detector communicates with the actuator 176, so that when the detector 182 b senses a predetermined characteristic in a particle, the actuator activates the first bubble valve 10 a to cause pressure variations in the reservoir 70 of the first bubble valve. The activation of the first bubble valves causes a transient pressure variation in the first side passage 174 a. The second side passage 174 b and the second bubble valve 10 b absorb the transient pressure variations in the measurement duct 166 induced via the actuator 176. Basically, the reservoir 70 b of the second bubble valve 10 b is a chamber having a resilient wall or contains a compressible fluid such as a gas. The resilient properties allow the flow of liquid from the measurement duct into the second side passage 174 b.
According to yet another embodiment, the cross-sectional dimensions of a microchannel including a bubble valve according to the teachings of the present invention may be varied locally to affect the pressure within the microchannel interior. For example, the microchannel may be narrowed or widened at certain locations to increase or decrease the capillary forces acting on a fluid in the microchannel interior. One of ordinary skill in the art will be able to determine a suitable cross-sectional dimension to achieve a desired pressure within the microchannel interior.
The bubble valve of the present invention may be implemented in a variety of microfluidic devices used for many applications. In a particular application, the bubble valve is implemented in a flow-cytometer based instrument for sorting or physically separating particles of interest from a sample or for measuring selected physical and chemical characteristics of cells or particles in suspension as they travel past a particular site. The bubble valve may also be employed in devices for sequencing or manipulating DNA, medical diagnostic instruments, devices for drug discovery, chemical analysis and so on.
The present invention provides an improved system and method for regulating fluid flow in a microchannel for a variety of applications. The bubble valve of the present invention is easy to operate and control, simple to manufacture and economical. In addition, the bubble valve does not adversely affect the liquid in the microchannel. The bubble valve effectively controls the flow of liquids in microfluidic systems, without heating the fluid and without complex on-chip circuitry.
The present invention has been described relative to an illustrative embodiment. Since certain changes may be made in the above constructions without departing from the scope of the invention, it is intended that all matter contained in the above description or shown in the accompanying drawings be interpreted as illustrative and not in a limiting sense.
It is also to be understood that the following claims are to cover all generic and specific features of the invention described herein, and all statements of the scope of the invention which, as a matter of language, might be said to fall therebetween.
Having described the invention, what is claimed as new and protected by Letters Patent is:
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|U.S. Classification||137/827, 137/807, 137/830, 137/831, 204/601, 137/806|
|International Classification||B01L3/00, G01N15/14, B07C5/34, F15C5/00, F16K99/00|
|Cooperative Classification||Y10T436/25375, Y10T137/2202, Y10T137/2196, Y10T137/2224, Y10T137/0396, Y10T137/2082, Y10T137/2213, Y10T137/0318, Y10T137/2191, Y10T137/2076, Y10T137/2207, Y10T137/0497, G01N2015/149, F16K99/0046, B01L2400/0688, B01L2400/082, Y10T436/143333, F16K2099/008, F16K99/004, B01L2200/0636, B01L2300/0864, F16K99/0036, F16K2099/0084, B01L2300/089, B07C5/34, F16K99/0034, F16K99/0017, B01L2400/0415, B01L3/502761, B01L2300/0816, F16K2099/0074, B01L2200/0647, B01L3/502738, F16K99/0001, B01L3/502776, B01L2400/06, F16K99/0019, F16K99/0048, Y10T29/49405|
|European Classification||B01L3/5027H, B01L3/5027E, F16K99/00M2G, F16K99/00M4C6, F16K99/00M4B, F16K99/00M4B4, F16K99/00M4, F16K99/00M2F, F16K99/00M4C4, B07C5/34, F16K99/00M|
|Sep 4, 2002||AS||Assignment|
|May 29, 2003||AS||Assignment|
Owner name: COVENTOR, INC., NORTH CAROLINA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:GILBERT, JOHN RICHARD;BOHM, SEBASTIAN;DESHPANDE, MANISH;REEL/FRAME:014110/0899;SIGNING DATES FROM 20030325 TO 20030418
|Oct 30, 2003||AS||Assignment|
|Oct 25, 2004||AS||Assignment|
|Jul 2, 2005||AS||Assignment|
Owner name: MASSACHUSETTS DEVELOPMENT FINANCE AGENCY, MASSACHU
Free format text: SECURITY AGREEMENT;ASSIGNOR:CYTONOME, INC.;REEL/FRAME:016216/0145
Effective date: 20050630
|Oct 20, 2008||REMI||Maintenance fee reminder mailed|
|Apr 10, 2009||SULP||Surcharge for late payment|
|Apr 10, 2009||FPAY||Fee payment|
Year of fee payment: 4
|Nov 17, 2009||AS||Assignment|
Owner name: CYTONOME/ST, LLC,MASSACHUSETTS
Free format text: CONFIRMATORY ASSIGNMENT;ASSIGNOR:CYTONOME, INC.;REEL/FRAME:023525/0158
Effective date: 20091020
|Oct 12, 2012||FPAY||Fee payment|
Year of fee payment: 8
|May 15, 2013||SULP||Surcharge for late payment|
|Mar 24, 2015||AS||Assignment|
Owner name: COMPASS BANK, TEXAS
Free format text: SECURITY INTEREST;ASSIGNOR:CYTONOME/ST, LLC;REEL/FRAME:035310/0670
Effective date: 20150318